Psoriasis is an inflammatory skin disease which affects 2-3% of the population. Of growing interest is the link between psoriasis and the development of cardiometabolic comorbidities, such as diabetes and cardiovascular disease. Hence, individuals with severe PSO (over 10% body surface coverage) have about 5-year shorter life expectancy. To better understand our findings from our large ongoing cohort study in psoriasis, HL-06193-05, we have initiated a set of complementary human cellular, murine and pre-clinical in vitro studies to dissect associations to provide mechanistic insight. Our approach involves three projects which are independent yet synergistic. Murine studies involve use of a psoriasis Rac-1 mouse and varying stimuli and exposures to understand the effect of chronic dermal inflammation on CMD outcomes. Cellular studies utilize primary human cells obtained from patients with psoriasis, and then those cells undergo various in vitro exposures to understand physiological differences in the cellular responses. Finally, we have an interest in proteins which are uniquely modulated in psoriasis to better understand both the pathogenesis of psoriasis, but also of PSO CMD.